P2X7 Receptor, Inflammation and Neurodegenerative Diseases (NeuroInfiam)

P2X7 Receptor, Inflammation and Pathophysiology of Neurodegenerative Diseases

Parkinson disease (PD) is a chronic degenerative disease characterized by a progressive loss of dopaminergic neurons in the substantia nigra. Its pathophysiological mechanisms are still partially unknown; a main role seems to be played by chronic neuroinflammation. A few reports have addressed the possible involvement of the inflammasome in PD, just describing the protective effect of P2X7 purinergic receptor (P2X7R) blockers in murine models of the disease and in microglial cells, where NLRP3 is activated by α-Synuclein, triggering a neuroinflammation that contributes to degeneration of dopaminergic neurons. It is still unclear whether, in addition to the increased brain expression and function of the nucleotide-binding domain, leucine-rich repeat, pyrin domain containing type 3 (NLRP3) inflammasome platform, a systemic activation of such complex might participate in the pathogenesis of PD, which could be the role of the P2X7R in this scenario, and whether such patterns undergo any specific epigenetic regulation. The present study has been designed to address these issues.

Study Overview

• Status: Completed
• Conditions: Neuro-Degenerative Disease
• Intervention / Treatment: Drug: Memantine, Dopamine receptor-agonists

Detailed Description

The day of the study patientes underwent a complete clinical evaluation and assessment of psycho-physical abilities using specific test such as Mini-Mental State Examination (MMSE), Cognitive Alzheimer's Disease Assessment Scale (ADAS-Cog), Clinical Dementia Rating Scale, Unified Parkinson's Disease Rating Scale (UPDRS). Blood samples were collected from an antecubital vein to assess serum and plasma aliquots for blood routine analysis and RNA and protein extraction from circulating lymphomonocytes.

To explore a putative epigenetic regulation of such complex scenario some circulating miRNAs likely involved in the pathogenesis of neurological diseases and neuro-inflammation will be measured.

Expression and functional activity of P2X7R-inflammasome complex will be measured by PCR and WB. Acute phase cytokines inflammasome-related levels will be determined by ELISA. Biochemical parameters (fasting glucose, lipid profile, serum creatinine, uric acid) will be measured by standard methods in the biochemistry laboratory of the University Hospital in Pisa. The same determinations will be repeated after one year from the first visit.

• Study Type: Observational
• Enrollment (Actual): 50

Contacts and Locations

Study Locations

• Italy
  • Pisa, Italy, 56125
    • University of Pisa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

The study consecutively enrolled 50 newly-diagnosed, treatment-naive PD or AD individuals among those referring to the Neurology Unit, University Hospital in Pisa, Italy.

Description

Inclusion Criteria:

• newly-diagnosed PD or AD;
• no previous specific treatment;
• no systemic inflammatory or immunological disease and/or cancer;
• no anti-inflammatory drugs assumed in the three months preceding the enrolment;
• patients able to consent.

Exclusion Criteria:

• history of strokes or any neurological disease;
• patients assuming neuroleptic drugs;
• atypical symptoms at onset.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
PD + AD; Patients with newly-diagnosed (onset of suggestive symptoms not later than 3 months) Parkinson disease (PD) or Alzheimer disease (AD) with no previous specific treatment, no anti-inflammatory drugs assumed in the three months preceding the enrolment and no chronic inflammatory diseases or cancer.	Drug: Memantine, Dopamine receptor-agonists; The study do not provide any experimental drugs. Patientes will receive treatment routinary used by Neurologist for these diseases.; Other Names: Memantine: Ebixa. Dopamine receptor-agonists: Sinemet, Sirio.
Control group; An age and gender matched control group (n=50) was formed, on a volunteer basis, by the spouse of the probands participating in the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in P2X7R-inflammasome activity	NLRP3-ASC-Caspase-1 activity is measured using RT-PCR	each patient will be assessed one year after diagnosis
Change from baseline in NFkB activity	NFkB activity is measured using RT-PCR	each patient will be assessed one year after diagnosis
Change from baseline in serum α-synuclein	Circulating levels of α-synuclein are determined using high sensitivity Quantikine enzyme-linked immunosorbent assay (ELISA) and express as [ng/ml]	each patient will be assessed one year after diagnosis
Change from baseline in serum IL-1β	Circulating levels of IL-1β are determined using high sensitivity Quantikine enzyme-linked immunosorbent assay (ELISA) and express as [pg/ml]	each patient will be assessed one year after diagnosis
Change from baseline in serum IL-18	Circulating levels of IL-18 are determined using high sensitivity Quantikine enzyme-linked immunosorbent assay (ELISA) and express as [pg/ml]	each patient will be assessed one year after diagnosis
Change from baseline in circulating levels of microRNA miR-30 and miR-7	Circulating levels of microRNA miR-30 and miR-7 are measured using TaqMan Advanced MicroRNA Assays	each patient will be assessed one year after diagnosis

Collaborators and Investigators

• Sponsor: University of Pisa
• Investigators: Principal Investigator: Anna Solini, MD, PhD, Univeristy of Pisa

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 20, 2017
• Primary Completion (ACTUAL): December 30, 2018
• Study Completion (ACTUAL): March 30, 2019

Study Registration Dates

• First Submitted: April 10, 2019
• First Submitted That Met QC Criteria: April 15, 2019
• First Posted (ACTUAL): April 17, 2019

Study Record Updates

• Last Update Posted (ACTUAL): August 13, 2019
• Last Update Submitted That Met QC Criteria: August 10, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Parkinson disease; Alzheimer disease; P2X7 receptor
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Inflammation; Neurodegenerative Diseases; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Protective Agents; Cardiotonic Agents; Dopamine Agents; Sympathomimetics; Antiparkinson Agents; Anti-Dyskinesia Agents; Dopamine; Memantine; Dopamine Agonists
• Other Study ID Numbers: AS0002

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No